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Rationale: Microarray technology is widely employed for studying the molecular mechanisms underlying complex diseases. However, analyses of individual diseases or models of diseases frequently yield extensive lists of differentially expressed genes with uncertain relationships to disease pathogenesis. Objectives: To compare gene expression changes in a heterogeneous set of lung disease models in order to identify common gene expression changes seen in diverse forms of lung pathology, as well as relatively small subsets of genes likely to be involved in specific pathophysiological processes. Methods: We profiled lung gene expression in 12 mouse models of infection, allergy, and lung injury. A linear model was used to estimate transcript expression changes for each model, and hierarchical clustering was used to compare expression patterns between models. Selected expression changes were verified by quantitative polymerase chain reaction. Measurements and Main Results: A total of 24 transcripts, including many involved in inflammation and immune activation, were differentially expressed in a substantial majority (9 or more) of the models. Expression patterns distinguished three groups of models: (1) bacterial infection (n 5 5), with changes in 89 transcripts, including many related to nuclear factor-kB signaling, cytokines, chemokines, and their receptors; (2) bleomycin-induced diseases (n 5 2), with changes in 53 transcripts, including many related to matrix remodeling and Wnt signaling; and (3) T helper cell type 2 (allergic) inflammation (n 5 5), with changes in 26 transcripts, including many encoding epithelial secreted molecules, ion channels, and transporters. Conclusions: This multimodel dataset highlights novel genes likely involved in various pathophysiological processes and will be a valuable resource for the investigation of molecular mechanisms underlying lung disease pathogenesis.

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Background-Allergic asthma results from inappropriate Th2-mediated inflammation. Both IL-4 and IL-13 contribute to asthma pathogenesis, but IL-4 predominantly drives Th2 induction, while IL-13 is necessary and sufficient for allergen-induced AHR and goblet cell hyperplasia. Although these 2 cytokines share signaling components, the molecular mechanisms by which they mediate different phases of the allergic asthma response remain elusive.

Alternatively spliced Tissue Factor (asTF) is a secreted form of Tissue Factor (TF), the trigger of blood coagulation whose expression levels are heightened in several forms of solid cancer, including pancreatic ductal adenocarcinoma (PDAC). asTF binds to β1 integrins on PDAC cells, whereby it promotes tumor growth, metastatic spread, and monocyte recruitment to the stroma. In this study, we determined if targeting asTF in PDAC would significantly impact tumor progression. We here report that a novel inhibitory anti-asTF monoclonal antibody curtails experimental PDAC progression. Moreover, we show that tumor-derived asTF is able to promote PDAC primary growth and spread during early as well as later stages of the disease. This raises the likelihood that asTF may comprise a viable target in early- and late-stage PDAC. In addition, we show that TF expressed by host cells plays a significant role in PDAC spread. Together, our data demonstrate that targeting asTF in PDAC is a novel strategy to stem PDAC progression and spread.

IL-4 and IL-13 are each bound by soluble receptors (sRs) that block their activity. Both of these sRs (sIL-4Rα and sIL-13Rα2) are present in low nanogram per milliliter concentrations in the serum from unstimulated mice, but differences in affinity and half-life suggest differences in function. Serum IL-4/sIL-4Rα complexes rapidly dissociate, releasing active IL-4, whereas sIL-13Rα2 and IL-13 form a stable complex that has a considerably longer half-life than uncomplexed IL-13, sIL-13Rα2, IL-4, or sIL-4Rα. Approximately 25% of sIL-13Rα2 in serum is complexed to IL-13; this percentage and the absolute quantity of sIL-13Rα2 in serum increase considerably during a Th2 response. sIL-13Rα2 gene expression is up-regulated by both IL-4 and IL-13; the effect of IL-4 is totally IL-4Rα-dependent while the effect of IL-13 is partially IL-4Rα-independent. Inhalation of an IL-13/sIL-13Rα2 complex does not affect the expression of IL-13-inducible genes but increases the expression of two genes, Vnn1 and Pira-1, whose products activate APCs and promote neutrophilic inflammation. These observations suggest that sIL-4Rα predominantly sustains, increases, and diffuses the effects of IL-4, whereas sIL-13Rα2 limits the direct effects of IL-13 to the site of IL-13 production and forms a stable complex with IL-13 that may modify the quality and intensity of an allergic inflammatory response.